Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we defined severe mood dysregulation(SMD)to capture youth with extremely severe irritability and symptoms of hyperarousal. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria(DMDD)in DSM-5. Since the inception of this project (ZIA MH002786-17), approximately 375 highly irritable (i.e., those with SMD, DMDD, or sub-threshold DMDD) have been recruited into the project, along with more than 100 youth with ADHD. (Many DMDD patients also have ADHD, and youth with ADHD tend to have less irritability than those with DMDD but more than healthy youth, making them an appropriate comparison group for your work.) Approximately 40 new patients were recruited this year. Youth with DMDD suffer severe psychiatric impairment, in terms of medications received, psychiatric hospitalizations, and standardized measures of function. As noted above, irritability is one of the most common psychiatric symptoms in children, but there has been little brain-based research devoted to it, and there are few evidence-based treatments. This year, we published a translational mechanistic model of irritability suggesting that core deficits in pediatric irritability include aberrant responses to frustration, aberrant approach responses to threat, and deficits in instrumental learning that prevent adaptation to changes in environmental contingencies. Irritability is particularly well-suited for the transdiagnostic, translational approach of the Research Domain Criteria (RDoC). Our work involves examining irritability characterized as a continuous variable, in DMDD and other groups with irritability, including youth with anxiety disorders or ADHD. Our neuroimaging work includes the use of frustrating tasks, since a hallmark of irritability is difficulty tolerating frustration. Previously, we demonstrated behavioral and neural differences between irritable and non-irritable youth during a frustrating attentional task. We improved that paradigm and obtained fMRI data from approximately 200 youth with DMDD, ADHD, and/or anxiety disorders, as well as healthy youth. In a manuscript recently accepted for publication, we found that irritability is associated with increased prefrontal and striatal engagement when youth attempt an attention orienting task after receiving frustrating feedback. Since prefrontal engagement is important in emotion regulation, one interpretation of this finding is that prefrontal emotion regulation mechanisms are less efficient in irritable vs. non-irritable youth. Alternatively, in irritable youth, increased prefrontal engagement may be required after frustration to down-regulate exaggerated subcortical limbic responses e.g., in the striatum. These effects of irritability are present even when ADHD and anxiety are taken into account. We have piloted two additional frustration tasks. The second frustration task differs from the first in the timing of frustration (short blocks of frustration, interspersed randomly with non-frustrating blocks, vs. a long block of non-frustration followed by a long bout of frustration) and in the cognitive task (attention orienting vs. cognitive flexibility). This second task allows us to test whether, across different task timing and cognitive tasks, increased irritability is associated with increased prefrontal engagement after frustration. We are now analyzing data from 80 healthy youth or those with DMDD, anxiety, or ADHD. Our third frustration task allows us to determine if irritability is associated with instrumental learning deficits at baseline and after frustration. Instrumental learning is the process by which people learn which of their behaviors will be rewarded. Deficits in such learning could lead to increased frustration in irritable youth. We successfully piloted this task outside the scanner and are now acquiring imaging data. Children typically present with multiple symptoms and diagnoses. It is important to identify pathophysiological mechanisms specific to different symptoms, and how the neural mechanisms mediating different symptoms interact. Such research furthers efforts toward personalized medicine. We are interested in neural mechanisms that differentiate anxiety and irritability, given cross-sectional and longitudinal associations between these traits and possible shared circuitry mediating them. Both irritable and anxious youth have an attention bias toward threatening faces. Therefore, we scanned approximately 200 children with a range of common symptoms, including anxiety, irritability, and ADHD, while they completed an attention bias task. In a manuscript published this year, we used cutting-edge statistical techniques to dissociate neural activation associated with parent- or child-reported irritability or anxiety. We found that irritability is associated with increased amygdala, striatal, and prefrontal engagement when subjects were asked to attend away from threat. In contrast, anxiety was associated with normal neural activity but abnormal connectivity between prefrontal and limbic regions. A major focus of our work is treatment. We completed our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability. In a sample of 49 youth, we demonstrated that indeed, stimulant plus citalopram is more effective in reducing irritability than is stimulant plus placebo. These data are currently being prepared for publication. Stimulant and SRI treatment tend to have fewer side-effects than atypical antipsychotic treatment, which is used frequently in youth with severe irritability. Therefore, this work has considerable public health importance. We recently developed and are testing two novel psychosocial approaches to treating irritability. The first involves computer-based training designed to shift a subject's perception of ambiguous faces from angry toward happy. In work published last year, we found that youth with DMDD tend to judge ambiguous faces as angry rather than happy; that we can change this judgment with computer-based training; and that this is associated with decreased irritability. This was an open trial, without a control condition. In 2016, we began a controlled trial of this new Interpretation Bias Treatment, along with brain imaging before and after training. Our target enrollment is 40 youth, and 35 have completed the protocol. Therefore, we anticipate finishing this trial soon and preparing the results for publication. This year, we completed and published an open pilot study of a manual-based cognitive behavioral treatment targeting irritability. This treatment has a strong emphasis on behavioral techniques i.e., exposing the child to tolerable, but frustrating situations, to improve the child's ability to tolerate such situations. The treatment is modelled on exposure therapy for anxiety disorders, and draws heavily on our neuroscience-based model of irritability, including irritable children's hypothesized deficits in the process and content of instrumental learning, and their aberrant responses to frustration. We designed and are now enrolling subjects for a multiple baseline design study of this new treatment. Such a design allows for more structured piloting whose results can be subjected to statistical analysis. Imaging on the first frustration paradigm and the threat paradigms, described above, will be conducted pre and post treatment. Outcome variables will include not only clinical ratings, but also real-time parent and child reports of temper outbursts using ecological momentary assessment.